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Sympathetic Nervous System Mediated Alterations in the Immunological and Behavioral Effects of Social Defeat

Hanke, Mark L.

Abstract Details

2010, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
During physiological or psychological stress, catecholamines produced by the sympathetic nervous system regulate the immune system. Previous studies report that the activation of β-adrenergic receptors (βARs) mediate the actions of catecholamines and increases pro-inflammatory cytokine production in a number of different cell types. Social disruption stress is a stressor that increases trafficking of immune cells from the bone marrow, induces glucocorticoid insensitivity of peripheral CD11b+ myeloid cells, alters the immune response to viral and bacterial challenges, and promotes long-lasting anxiety-like behavior in mice. The purpose of this study was to determine the degree to which the sympathetic nervous system affects the activation, priming and glucocorticoid insensitivity of splenocytes after repeated social defeat. Here we report that repeated social defeat increased catecholamine levels in the blood and spleen and that the increased anxiety-like behavior, splenomegaly, and plasma interleukin(IL)-6 induced by social disruption stress (SDR), were each reversed by pre-treatment with the β-adrenergic antagonist propranolol. Furthermore, propranolol pretreatment reversed the SDR-induced increase of TLR2 and TLR4 expression on the surface of splenic CD11b+ cells. In addition, supernatants from propranolol-treated socially defeated mice stimulated with lipopolysaccharide (LPS) contained less cytokines and propranolol pre-treatment abrogated the glucocorticoid insensitivity of CD11b+ cells ex vivo when compared to splenocytes from socially defeated vehicle mice. Furthermore we show that social defeat increased c-Fos staining in brain regions associated with fear and threat appraisal in a β-adrenergic dependent manner. Moreover, analysis by flow cytometry indicates that social defeat significantly increased the number of CD11b+/CD45high macrophages that traffic to the central nervous system. In addition, the surface expression of several inflammatory markers was increased on microglia (CD14, CD86, and TLR4) and macrophages (CD14 and CD86) after social defeat. mRNA analysis of the enriched microglia indicated that there was increased levels of inflammatory-related genes (IL-1β) and a reduction in glucocorticoid responsive genes (GILZ and FKBP51). These social defeat-dependent changes in enriched microglia were reversed by propranolol. To determine if the reactive phenotype of microglia predicted enhanced pro-inflammatory gene expression and glucocorticoid resistance, ex vivo cultures of enriched microglia were established. While glucocorticoids were anti-inflammatory in microglia cultures challenged with LPS, enriched microglia isolated from socially defeated mice produced significantly higher levels of MCP-1, IL-6, and TNF-α after LPS compared to control mice. Together, this study demonstrates that the anxiety-like behavior, immune activation and priming effects of social defeat result as a consequence of sympathetic nervous system activation in a β-adrenergic receptor dependent manner.
John Sheridan (Advisor)
William Lafuse (Committee Member)
Jonathan Godbout (Committee Member)
Michael Bailey (Committee Member)
160 p.

Recommended Citations

Citations

  • Hanke, M. L. (2010). Sympathetic Nervous System Mediated Alterations in the Immunological and Behavioral Effects of Social Defeat [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1283527905

    APA Style (7th edition)

  • Hanke, Mark. Sympathetic Nervous System Mediated Alterations in the Immunological and Behavioral Effects of Social Defeat. 2010. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1283527905.

    MLA Style (8th edition)

  • Hanke, Mark. "Sympathetic Nervous System Mediated Alterations in the Immunological and Behavioral Effects of Social Defeat." Doctoral dissertation, Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1283527905

    Chicago Manual of Style (17th edition)